This invention relates to fluorinating agents, especially to electrophilic fluorinating agents and in particular to novel triazinium compounds. The invention also relates to a method of fluorinating a substrate, especially an organic substrate using these fluorinating agents. The fluorinating agents are particularly useful for fluorinating electron-rich species, for example activated aromatic compounds (i.e. carrying electron-donating substituents) or overt or covert carbanions.
Fluorination is an important process in many areas of industry, in particular where the synthesis of specialty chemicals is concerned. Known fluorination methods are conveniently categorized according to the perceived manner in which the fluorinating agents provide fluorine for combination with an active site in an organic molecule, namely as fluorine atom (Fxc2x7), fluoride ion (Fxe2x88x92) or, conceptually, fluoronium ion (F+). Fluorinations involving fluorine atom are notoriously exothermic and non-selective, hence xe2x80x9clightxe2x80x9d strategic fluorination of organic compounds (that is, the introduction of one or two fluorine substituents or a trifluoromethyl group at key molecular sites) rests on the availability of versatile ranges of nucleophilic and electrophilic sources of fluorine. Of late, the use of N-fluoro compounds has become one of the most widely used methods for the selective formation of carbon-fluorine bonds via xe2x80x9celectrophilicxe2x80x9d mechanisms. A recent comprehensive review of this synthetic methodology contains no reference to Nxe2x80x94F reagents derived from triazines (see G. G. Furin in Methods of Organic Chemistry (Houben-Weyl): Volume E10a; Organofluorine Compounds (ed. B. Baasner, H. Hagemann, and J. C. Tatlow), Georg Thieme Verlag, Stuttgart, 1999, pp. 432-499.
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (so-called F-TEDA-BF4) is a known, commercially available (under the trade name xe2x80x9cSelectfluorxe2x80x9d) fluorinating agent and is useful as a general purpose fluorinating agent. However this material has only a moderate fluorinating power and is able to fluorinate benzene only under forcing conditions, for example under reflux for 24 hours. The chemistry of F-TEDA-BF4 has been reviewed by R. E. Banks in J. Fluorine Chemistry 87 (1998) 1-17, the whole content of which is incorporated herein by reference.
N-Fluoropyridinium salts and ring-substituted analogues thereof, e.g. N-fluoropyridinium triflate, are known for use as a fluorinating agent but have relatively low fluorinating power. U.S. Pat. No. 4,828,764 discloses that certain N-fluoro-N-perfluoroalkyl or perfluoroaryl sulfonamides including, inter alia, those of the formula RfSO2NFR are electrophilic fluorinating agents. In this formula Rf represents a perfluorinated C1-C30 alkyl, C3-C30 cycloalkyl, C6-C14 aryl substituted C1-C10 alkyl or a C6-C14 aryl group and R represents a C1-C30 alkyl, C3-C30 cycloalkyl, C6-C14 aryl substituted C1-C10 alkyl, or C6-C14 aryl group optionally substituted with one or more inert substituents including, inter alia, fluorine and, when Rf is trifluoromethyl, R alternatively can represent perfluoromethyl-sulfonamido. The preferred fluorinating agents are stated to be N-fluorobis-(trifluoromethanesulfonyl)imide (Rfxe2x95x90CF3 and Rxe2x95x90CF3SO2), known as DesMarteau""s Reagent, and N-fluoro-N-methyltrifluoromethanesulfonamide (Rfxe2x95x90CF3 and Rxe2x95x90CH3). DesMarteau""s Reagent is a powerful electrophilic fluorinating agent which is capable of converting benzene to fluorobenzene at room temperature but is hazardous, time-consuming and expensive to prepare, requiring eight or nine reaction steps from readily available material. Only a very limited number of other known fluorinating agents are strong enough to fluorinate benzene without forcing conditions but they often provide relatively low yields or require special precautions.
N-Fluorotriazinium salts of the following Formula A are known: 
wherein:
(i) Xxe2x95x90H and Yxe2x88x92xe2x95x90AsF6xe2x88x92(Ref. 1xe2x80x94see below)
(ii) Xxe2x95x90F and Yxe2x88x92xe2x95x90AsF6xe2x88x92(Ref. 2xe2x80x94see below)
(iii) Xxe2x95x90F and Yxe2x88x92xe2x95x90BF4xe2x88x92(Ref. 3xe2x80x94see below) and
(iv) Xxe2x95x90Cl and Yxe2x88x92xe2x95x90AsF6xe2x88x92(Refs. 2 and 4xe2x80x94see below).
The N-fluorotriazinium salts of Formula A are reported to be oxidizing agents of use in, for example, organometallic chemistry. The cationic component of compounds of Formula A in which X is H, F and Cl have been described as xe2x80x9coxidative fluorinatorsxe2x80x9d and a qualitative scale for their oxidizing strength and that of NF4+ has been computed ab initio (Ref. 3xe2x80x94see below).
Ref. 1=Broschag et al. Inorg. Chim. Acta, 205 (1993) 167-173;
Ref. 2=Schleyer et al. Inorg. Chem. 32 (1993) 1523-1524;
Ref. 3=Schulz and Klapxc3x6tke J. Organometal. Chem. 480 (1994) 195-197; and
Ref. 4=Broschag et al. Z. Anorg. Allg. Chem., 620 (1994) 1132-1136.
There is a statement in Schleyer et al. that 1-fluoro-2,4,6-trichloro-s-triazinium hexafluoroarsenate (Formula A; Xxe2x95x90Cl; and Yxe2x88x92xe2x95x90AsF6xe2x88x92) xe2x80x9cis a promising fluorination agentxe2x80x9d but no further details were provided or subsequently reported. It is believed that uses of the compounds of Formula A other than as oxidizing agents was not contemplated or investigated. In particular, there is no disclosure in the prior art of any of these compounds being evaluated as oxidative fluorinators (as distinct from non-fluorinating oxidizing agents) despite the computed values reported in Refs. 3 and 4.
We have now found that certain substituted triazinium salts having a fluorine atom on at least one of the triazinium nitrogen atoms provide excellent electrophilic fluorinating agents yet do not possess some of the drawbacks of known electrophilic fluorinating agents. These triazinium salts can be monomers represented by the following Formula I: 
in which:
three A moieties are independently CR, where each R is independently, hydrogen, halogen, hydroxyl, amino, cyano, perfluorothio, hydroxysulfonyl, halosulfonyl, hydrocarbyloxysulfonyl, or a carbon-containing substituent selected from the group consisting of optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups, and at least one R is neither hydrogen nor halogen;
two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and
Yxe2x88x92 is a counterion or group of counterions which are inert to chemical attack by fluorine.
The salts also can be oligomers or polymers of the salts of Formula I in which adjacent triazinium moieties are linked by a common R substituent.
In another aspect of the invention there is provided use of a compound of Formula I as an electrophilic fluorinating agent.
The invention provides electrophilic fluorinating agents which are triazinium compounds of the following Formula I: 
wherein:
three A moieties are independently CR, where each R is independently, hydrogen, halogen, hydroxyl, amino, cyano, perfluorothio, hydroxysulfonyl, halosulfonyl, hydrocarbyloxysulfonyl, or a carbon-containing substituent selected from the group consisting of optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups, and at least one R is neither hydrogen nor halogen;
two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and
Yxe2x88x92 is a counterion or group of counterions which are inert to chemical attack by fluorine,
and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent.
It is presently preferred that the triazinium compounds are 1,2,4-triazinium compounds of the following Formula IA or, especially, 1,3,5-triazinium compounds of the following Formula IB: 
wherein:
R1, R2 and R3 are, independently, hydrogen, halogen, hydroxyl, amino, cyano, perfluorothio, hydroxysulfonyl, halosulfonyl, hydrocarbyloxysulfonyl, or a carbon-containing substituent selected from the group consisting of optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups, and at least one of R1, R2 and R3 is neither hydrogen nor halogen;
Z1 and Z2 are independently nitrogen or a quaternary nitrogen atom; and
Yxe2x88x92 is a counterion or group of counterions which are inert to chemical attack by fluorine,
and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent.
Desirably the compound of Formula I is relatively pure and contains less than about 20%, more preferably less than about 10% and especially less than about 5% impurities so as to reduce the level of impurity carried into a reaction in which the compound is employed as a fluorinating agent. However, where the compound is of limited stability, it usually will be used without separation from the reaction mixture.
In another aspect of the invention there is provided use of a compound of Formula I as an electrophilic fluorinating agent.
Compounds of Formula I have a high fluorinating power which allows substrates, especially electron-rich species for example carbanionic or activated aromatic substrates, which are difficult to fluorinate using some known fluorinating agents to be fluorinated. Also compounds of Formula I may be employed to fluorinate substrates which may presently be fluorinated electrophilically using known fluorinating agents but under milder reaction conditions due to the effective fluorinating power of compounds of Formula I.
The said carbon-containing substituent(s) may be unsubstituted and contain only hydrogen and carbon atoms, and in the case of hydrocarbyloxy and hydrocarbylthio, also an oxygen or sulfur atom respectively, or they may be substituted and contain one or more heteroatoms for example oxygen, nitrogen, halogen and sulfur, and/or heterogroups, for example carbonyl, ester and amide links. Thus, optionally the carbon-containing substituent(s) may contain a heteroatom in the carbon chain and/or may be substituted with a substituent containing a heteroatom such as, for example, OH, alkoxy and halogen, for example chlorine, bromine and especially fluorine. One or more (including all) hydrogen atoms in the said carbon-containing substituent(s) may be substituted as desired.
A preferred embodiment of the invention provides electrophilic fluorinating agents of Formula I wherein at least one R, or at least one of R1, R2 and R3 for Formulae IA and IB, is hydrocarbyl, hydrocarbyloxy, hydrohalocarbyl, hydrohalocarbyloxy, perhalocarbyl, or perhalocarbyloxy, and Z, or Z1 and Z2 for formulae IA and IB, and Yxe2x88x92 are as defined above.
The hydrocarbyl and hydrocarbyloxy groups may be alkyl, alkenyl, aryl, aryloxy and alkoxy groups which optionally are substituted. Preferably the alkyl and alkoxy group have from about 1 to about 12 carbon atoms, more preferably about 1 to about 8 carbon atoms and especially about 1 to about 4 carbon atoms, for example methyl, ethyl, methoxy and ethoxy. Preferably the alkenyl group and aryl group have from about 2 to about 12, especially about 2 to about 8, carbon atoms and from about 6 to about 12, especially about 6 to about 9, carbon atoms respectively.
In one preferred embodiment, at least one R, or R1, R2 and/or R3 for Formulae IA and IB, is selected from the group consisting of hydrohaloalkyl groups, especially hydrofluoroalkyl groups, and perhaloalkyl groups, especially perfluoroalkyl groups. Examples of suitable perfluoroalkyl groups include trifluoromethyl, pentafluoroethyl and perfluorooctyl groups and examples of suitable hydrofluoroalkyl groups include 2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl and H(CF2CF2)pCH2 groups (where p is at least 2). Perhaloalkyl groups may be preferred in some cases due to the absence of a carbon-hydrogen bond which may be susceptible to electrophilic fluorination.
In another preferred embodiment for ease of synthesis, at least one R, or R1, R2 and/or R3 for Formulae IA and IB, is selected from the group consisting of hydrohaloalkoxy groups, especially hydrofluoroalkoxy groups, and perhaloalkyl groups, especially perfluoroalkyl groups. Examples of suitable perfluoroalkoxy groups include trifluoromethoxy, pentafluoroethoxy and perfluorooctoxy groups and examples of suitable hydrofluoroalkoxy groups include 2,2,2-trifluoroethoxy and 2,2,3,3-tetrafluoropropoxy. Particularly preferred are H(CF2CF2)pCH2O groups (where p is at least 2) which are readily available using known telomer alcohols of the corresponding formula H(CF2CF2)pCH2OH. In another preferred embodiment, at least one R, or R1, R2 and/or R3 for Formulae IA and IB, is a thio analogue of the aforementioned hydrohaloalkoxy and perhaloalkoxy groups, for example trifluoromethylthio (CF3S), or a perfluorothio group such as pentafluorothio (SF5).
The terms aryl and aryloxy include moieties which contain aliphatic as well as aromatic groups. Preferred aryl and aryloxy groups include phenyl, phenoxy, and groups of formula C6H5(CH2)r[OC2H4]qOt where q is 0 to 6, r is 0 to 8 and t is 0 or 1, which may be optionally substituted, preferably with fluorine.
It is especially preferred that all R substituents, or R1, R2 and R3 for Formulae IA and IB, are identical in a given compound. Examples of especially preferred compounds are those in which all R substituents, or all of R1, R2 and R3, are methyl, methoxy, trifluoromethyl or trifluoromethoxy groups. A practical advantage of all R substituents, or all of R1, R2 and R3, being the same group is the manufacture of the compound may be simplified and isomers or a mixture of compounds is less likely to be produced.
R, or R1, R2 and R3, may be selected so as to provide technical advantages to the compound of Formula I in addition to the fluorination characteristics such as improving the solubility of the compound in non-polar solvents and solvents of low polarity. Thus greater flexibility in chemical synthesis involving electrophilic fluorination is also provided by the compounds of Formula I.
The compounds of Formula I can be oligomers or polymers in which adjacent triazinium moieties are linked by a common R substituent, for example, a hydrocarbyl, perfluorohydrocarbyl or hydrocarbyldioxy group. Presently preferred linking groups are dioxyphenyl, di(oxycarbyl)phenyl, alkylenedioxy or bis(oxyaryl)alkylene groups, such as, for example, 1,5-dioxypent-2,4-diyl (i.e. xe2x80x94Oxe2x80x94CH2xe2x80x94CHxe2x80x94CH2xe2x80x94CHxe2x80x94CH2xe2x80x94Oxe2x80x94), 1,3-bis(p-oxyphenyl)prop-1,3-diyl (i.e. -p-OC6H4xe2x80x94CHxe2x80x94CH2xe2x80x94CHxe2x80x94C6H4O-p-), or 1,3-bis(m/p-oxymethylphenyl)prop-1,3-diyl (i.e. -m/p-OCH2C6H4xe2x80x94CHxe2x80x94CH2xe2x80x94CHxe2x80x94C6H4CH2O-m/p-).
The compounds of Formula I contain at least one fluorinated quaternary nitrogen atom in the triazinium ring and one or both of the other triazinium nitrogen atoms may be quaternary, preferably fluorinated, nitrogen. In a preferred embodiment both Z, or both Z1 and Z2 for Formulae IA and IB, are nitrogen and the most preferred compounds are those of the following Formula II: 
wherein R1, R2, R3 and Yxe2x88x92 are as defined above.
Examples of especially preferred compounds according to the invention are those having a triazinium cation as shown below in Formulae III to V. 


The counterion Yxe2x88x92 is resistant to chemical attack by fluorine and desirably is thermally stable and possesses low environmental toxicity. The counterion(s) can be any anion(s) which can be counterion(s) to the triazinium cation. The counterion(s) may have a single charge or a multiple charge or be a group of counterions so as to balance the charge of the triazinium moiety. Also the counterion may be a counterion to more than one mole of the triazinium cation, for example where the cation has a single charge and the counterion has a multiple charge.
Suitably the counterion is weakly nucleophilic. Suitable anions include fluoride; fluorosulfate (SO3Fxe2x88x92); alkanesulfonate, especially methanesulfonate (CH3SO3xe2x88x92); alkyl sulfate, especially methyl sulfate (CH3SO4xe2x88x92); perfluoroalkanesulfonate, preferably triflate (CF3SO3xe2x88x92) and nonaflate (C4F9SO3xe2x88x92); arenesulfonate, especially tosylate (i.e. p-toluenesulfonate, p-CH3C6H4SO3xe2x88x92); alkanecarboxylate; perfluoroalkanecarboxylate; tetrafluoroborate (BF4xe2x88x92); tetraphenylborate (Ph4Bxe2x88x92); hexafluorophosphate (PF6xe2x88x92); hexafluoroantimonate (SbF6xe2x88x92); hexafluoroarsenate (AsF6xe2x88x92); chlorate (ClO3xe2x88x92); and sulfate (SO42xe2x88x92xe2x95x902Yxe2x88x92), hydrogen sulfate (HSO4xe2x88x92) and F(HF)xxe2x88x92 where x is at least 1. Presently preferred counterions include fluoride, tetrafluoroborate, triflate, tosylate, hexafluoroarsenate and hexafluorophosphate.
Preferably, the compounds of Formula I are prepared using a solvent-based process which comprises contacting a triazine compound with a fluorine source under acidic conditions in a solvent which is inert under the process conditions.
Suitably the fluorine source is an electrophilic fluorine source such as, for example, fluorine gas or a mixture of fluorine gas and a neutral compound derivable from a fluorine-containing counterion Yxe2x88x92 by removing at least one fluoride ion from Yxe2x88x92, for example boron trifluoride. Preferably, the fluorine source is fluorine gas. While the fluorine gas may be used without dilution, in general, it is preferable to use fluorine gas diluted with an inert gas so that the volume of the inert gas is between about 99.9% and about 50% for controlling the vigorous reaction. Suitable inert gases include nitrogen, helium and argon.
The triazine compound to be fluorinated is suitably a compound of the Formula VI and may be obtained by subjecting a compound or a mixture of compounds of formula RCN to a known process for producing a triazine compound of formula (RCN)3, wherein R is independently R1, R2 or R3 as described herein: 
The fluorination process is carried out in the presence of an acid which may be a Brxc3x8nsted acid (organic or mineral) or a Lewis acid. The level of acid is suitably adjusted so as to reduce and desirably avoid double protonation of the triazine compound and to provide a yield (as determined by 19F NMR) of Fxe2x80x94N+ of at least about 20% and desirably of at least about 50%. Desirably the molar ratio of acid to triazine substrate is about 0.5 to about 2.5, preferably about 1 to about 2.2.
Preferable examples of Brxc3x8nsted acid have pKa in the range from about 12.4 to about 4.6 and include halogenated alcohols, for example chlorodifluoroethanol, dichlorofluoroethanol, chlorooctafluoro-t-butanol, trifluoroethanol, tetrafluoropropanol, pentafluoropropanol, hexafluoroisopropanol, octafluoropentanol, and nonafluoro-t-butanol. Fluorinated alcohols, particularly those which are free of chlorine, are especially preferred.
Other acids which are especially preferred include acids of the counterion Yxe2x88x92 described above, for example anhydrous hydrofluoric acid, hexafluoroantimonic acid, tetrafluoroboric acid and triflic acid, sulfuric acid, methanesulfonic acid, acetic acid and trifluoroacetic acid.
Brxc3x8nsted acids may be used in the form of a complex with ethers, water, alcohols, nitrites, carboxylic acids and the like and may be used in the form of an aqueous solution.
Preferably, the solvent is non-aqueous and it is presently particularly preferred that the solvent is acetonitrile, a halogenated, especially fluorinated, alcohol or, especially, nitromethane. In this connection, it is believed that there has not been any previous proposal to use nitromethane as a solvent, or for any other purpose, with any Nxe2x80x94F or +Nxe2x80x94F reagent.
If desired the same material may be used as both the acid and the solvent.
The reaction to produce compound of Formula I is carried out at a temperature at which the solvent is in the liquid phase and suitably at a sufficiently low temperature that reaction due to a free radical mechanism is reduced and suitably avoided. The particular temperature selected depends on the solvent and also the reactants. By way of example only, the reaction suitably may be carried out at a temperature of about xe2x88x9240 to about 10xc2x0 C. A temperature of about xe2x88x9240 to about xe2x88x9220xc2x0 C. is preferred for acetonitrile and a temperature of about xe2x88x9210 to about 5xc2x0 C is preferred for hexafluoroisopropyl alcohol. The reaction may be carried out at elevated pressure although this is not essential.
Fluorination of the triazine compound may be carried out using a stirred-tank batch reactor. Where the fluorine source is gaseous, the fluorine source is suitably admitted either as neat gas at sub-atmospheric pressure or as a continuous flow of fluorine blended with nitrogen or other inert diluent at about atmospheric pressure. Advantageously, the process for producing compound of Formula I may be operated as a continuous process.
The invention also provides a method of producing a fluorinated substrate which comprises contacting a substrate with a compound of Formula I so as to fluorinate the substrate.
The compounds of Formula I may be used as electrophilic fluorinating agents in a similar manner to Selectfluor(trademark) and in manner know in the art (see, for example, R. E. Banks et al J. Chem. Soc., Perkin Trans. I, 1996, 2069). The fluorinating agent may be contacted with the substrate neat and optionally at elevated temperature. If desired the fluorination process may be carried out in a solvent, for example acetonitrile or, especially, nitromethane. As mentioned above, it is believed that there has not been any previous proposal to use nitromethane as a solvent, or for any other purpose, with any Nxe2x80x94F or +Nxe2x80x94F reagent.
When a compound of Formula I has been used in a fluorination reaction and so depleted in fluorine, it may be recovered and regenerated by introducing the fluorine source for reuse in further fluorination reactions.
The compounds of Formula I may be used to fluorinate organic compounds, for example nucleosides, nucleoside bases and steroids, or cationic organometallic compounds for example cyclopentadienides. They are especially useful in fluorinating carbanionic and/or aromatic substrates.
In a preferred embodiment of the fluorination aspect invention, a fluorinated steroid is prepared by contacting a steroid or a suitable derivative such as a steroidal enol acetate or silyl enol ether with a fluorinating agent of Formula I optionally in the presence of a solvent and optionally at elevated temperature. Preferably, the steroid is fluorinated at the 6 and/or 16 position.
Compounds of Formula I may be isolated or used without separation from the reaction mixture. If desired, the reaction mixture may be fed to a separate fluorination reactor or the compound of Formula I may be purified or otherwise treated prior to use.
Accordingly, the invention also provides a method of producing a fluorinated substrate which comprises contacting, preferably under acidic conditions, a triazine compound with a fluorine source in a solvent, which is inert under the process conditions, such that at least one of the nitrogen atoms in the triazine compound is fluorinated to produce a compound of Formula I and contacting, in situ or subsequently, the compound with a substrate to be fluorinated.
The invention is illustrated by the following non-limiting Examples.